Links of interest  Vascular Research Foundation

Introduction:

Arherosclerosis (also known as arterioslerotic vascular disease or ASVD) is an inflammatory disease characterized by intense immunological activity. It involves the formation in the arteries of lesions that are characterized by inflammation, lipid accumulation, cell death and fibrosis. Over time, these lesions, which are known as atherosclerotic plaques, mature and gain new characteristics. The atherosclerotic lesion typically comprises fatty streaks that later develop into fibrous plaques. The initial fatty streaks are characterized by the presence of lipid laden foam cells, mainly macrophage in origin. Fatty streaks may regress or progress via a transitional lesion to fibrous plaques. 

Atherosclerosis is a complex, multifactorial, and chronic disease influenced by a wide variety of genetic, environmental, and behavioral activites. (Witztum, Circulation, 1998, 98, 2785-2787). The most severe clincial events follow the ruptures of a plaque which exposes the prothrombotic material in the plaque to the blood and causes sudden thrombotic occlusion of the artery at the site of disruption. In the heart, atherosclerosis can lead to myocardial infarction and heart failues, whereas in the arteries that perfuse the brain, it can cause ischaemic stroke and transient ischaemic attacks.

Atherosclerosis is the most common pathologic process leading to cardiovascular disease (CVD), including myocardial infarction (MI) and Stroke.

Several autoimmune rheumatic conditions, including rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome, are characterized by enhanced atherosclerosis (Sherer, Nature Clinical Practice Rheumatology, 2(2), 2006).

Definitions:

Cholesterol: is a waxy, fat-like substance found in the walls of cells in all parts of the body, form the nervous system to the liver to the heart. The body uses cholesterol to make hormones, bile acids, vitamin D and other substances. As with oil and water, cholesterol (which is fatty) and blood (which is watery) do not mix. So cholesterol travels in packages called lipoprotines, which have fat (lipid) inside and prtoein outside.. The two main kinds of lipoproteins which carry chaolesterol in the blood are LDL and HDL. If there is too much cholesterol in the bood, some of the excess can become trapped in artery walls. Over time, this builds up and is called plaque. The plaque can narrow vessels and make them less flexible, a condition called artherosclerosis or “hardening of the arteries”. All adults age 20 and older should have their cholesterol levels checked at least once every 5 years. The recommended cholesterol test is called a “liporotein profile” which measures levels of total choelsterol (which includes the cholesterol in all lipoproteins, LDL, HDL and triglycerides. The lipoprotein profile is odne after a 9-12 hour fast. The levels are measrued as milligrams of cholesterol per deciliter of blood, or mg/dL. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005).

Less than 200 mg/dL is a desirable cholesterol level. 200-239 mg/dL is boerderline high and 240 mg/dL and above is high. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Low density lipoprotein (LDL): is also called the “bad” cholesterol because it carries cholesterol to tissues, including the arteries. Most of the chorlesterol in the blood is the LDL form. The higher the level of LDL cholesterol in the blood, the greater your risk for heart disease. (The amin gol in treating high choelsterol is to lower your LDL level. Studies have proven that lowering LDL can prevent heart attaccks and reduce deaths from heart disease. “Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Less than 100 mg/dL is an optimal LDL level. 100-129 mg/dL is abvoe optimal, 130-159 mg/dL is borderline high, 160-189 mg/dL is high and 190 mg/dL and above is very high. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

High density lipoprotein (HDL): is called the “good” cholesterol because it takes cholesterol form tissues to the liver, which removes it from the body. A low level of HDL incrases your risk for heart disease. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Less than 40 mg/dL is a major heart disease risk factor. 60 mg/dL and above gives some protein agaisnt heart disease. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Triglycerides: are produced in the liver and are naother type of fat found in the blood and in food. Causes of raised triglycerides are overweight/obesity, physical inactivity, cigarette smoking, excess alcohol intake and a diet very hihg in carbohydrates (60% of caloreis or higher). Recent research indicates that triglyceride levels that are borderline high (150-199 mg/dL) or high (200-499 mg/dL) may increase your risk for heart disease. (lelves of 500 mg/dL or mroe need to be lowered with medication to prvent the pancrease form becoming inflamed. A triglyceride level of 150 mg/dL or higher also is one of the risk factors of the metabolic syndrome. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Risk Factors

The most important risk factors for atheroslerosis invlude smoking, hypertension, dyslipidemia (increased concentration of LDL and decreased concentration of HDL), diabetes, aging, and a family history of premature atherosclerosis. 

Hypercholesterolemia is one of the most important risk factors for atherosclerosis. The mechanisms by which elevated levels of liporproteins, chiefly the apoB containing liporoteins such as LDL, cause an acceleration of atherogenesis are only incompletely understood (Witztum, Circulation , 1998, 98, 2785-2787.

Saturated or trans fat raises your LDL cholesterol level more than anything else in your diet. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Mechanisms of Pathogenesis

The mechanism of atherosclerosis is not well understood (US 11/753799). However, atherosclerosis is a chronic inflammatory disorder. Acute phase reactants (e.g., C-reactive protein, complement proteins) are enriched in fatty streaks and later stages of atherosclerotic lesions. (US 6040147)

High Blood Pressure (Hypertension): can damage the endothelium of blood vessels by stretching them and hardening over time. An inujured endothelium allows LDL cholestoral (“bad cholesteroal”) to enter the lining of the artery which can then build up and cause plaques. Plaques can latter rupture and cause blood clots, resulting in stroke or heart attacks. High blood pressure typically has no symptoms and only about 30% of people have it under control. About 50% of people will have hypertension by the age of 60. Blood pressure higher than 130/80 is seen in a large percentage of people who have their first heart attack and stroke. (normal blood pressure is less than 120 over less than 80). 

C Reactive Protein: In one clinical trial, base line plasma levels of C-reactive protein independently predicted risk of first time myocardial infarction and stroke in apparently healthy individuals (US 6040147). 

Role of Chemokines: Data obtained using knockout mice show a key role for CC-chemokine ligand 2 (CCL2; also known as MCP1) and its receptor, CC-chemokine receptor-2 (CCR), in the initiation of atheroslerosis. Absence of CCL2 or CCR2 limits the entry of monocytes and T cells into the arterial intima and inhibts atherogenesis.

Macrophages and vascular cells of the forming plaques also product the T-cell attractants CCL5 (also known as RANTES), CXC-chemoine ligand 10 (CXCL10; also known as IP10) and CXCL11 (also known as ITAC).

Role of Cell Adhesion Molecules;  Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions such as atherosclerosis. Leukocyte recruitment to the endothelium is started when inducible adhesion molecule receptors on the surface of endothelial cells interact with counterreceptors on immune cells. Polyunstaurated fatty acids and their hydroperoxides which are important components of oxidatively modified LDLs (see below) induce the expression of VCAM-1. US 5846959 discloses a treatment for atheroscelrosis and other inflammatory diseases that are mediated by VCAM-1 which includes the inhiition of the formation of oxidized polyunsaturated fatty acids which involves administering an effective amount of a substace that prevents the oxidation of a polyunsaturated fatty acid. 

Elevated LDL: is a major risk factor for premature coronary artery disease. The onset of this disorder is marked by the appearance of lipid laden macrophages in the intima of the arterial wall. 

LDL oxidation: It has been hypothesized that modification of low-density lipoprotein (LDL) into oxidatively modified LDL (ox-LDL) by reactive oxygen species is a central event that initiates and propagates atherosclerosis. This hypothesis is supported by the fact that lipoprotein like particles with properties consistent with oxidative damage have been isolated from animal and human aortic lesions. Oxidized LDL is a chemoatttractant for monoctyes and T lymphocytes and also inhibits macrophage motility, thereby promoting retention of macrophages in the arterial wall. 

1. Mechanism of LDL oxidation: The mechanisms that oxidatively damage lipoproteins remain poorly understand but cultured endothelial cells, smooth muscle cells and monocyte derived macrophages modify LDL by reactions that require iron or copper implicating cellular mechanisms and free metal ions in lipoprotein oxidation. Activated monocytes oxidatively modify LDL in vitro by a mechanism that is inhibited by superoxide dismutase, catalase, and metal chelators, suggesting the involvement of O2.- and H2O2. H2O2 is formed by dismutation of O2.- produced by a membrane associated NADPH oxidase. Activated monocytes also secrete a heme enzyme myeloperoxidase, that uses H2O2 as a substrate to generate products that can oxidize lipids and proteins. One product is hyperochlorous acid (HOCL), which is formed from CL-. This potent cytotoxin plays a critical role in host defenses against invading bacteria, viruses, and tumor cells, but it may also injure normal tissue. Another product of the myeloperoxidase-H2O2 system at plasma concentrations of CL- and amino acids is tyrosyl radical.  (Daugherty, “Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions” J. C.in. Invest, 94 1994, 437-444). 

2. Measurement of LDL oxidation: Direct methods for oxidation include F2 isoprostanes, antibody to oxidized LDL, antioxidant status, and breath volatile hydrocarbons.

F2 isoprostanes elevation: F2 isoprostanes are prostaglandin-like compounds formed in vivo from free radical catalyzed peroxidation of arachidonic acid. The F2 isoprostanes are formed by oxidation of arachidonic acid esterified to phosphlipids in cellular membranes. They can also form when LDL undergoes either cell or copper-meidated oxidation. They are released by a phospolipase actvity and circulate in the palsama in free form or as phospholipid esters and can be excreted in urine. ((Witztum, Circulation, 98, 2785-2787, 1998). They are generally measured by gas chromatography-mass spectrometry. F2 isoporstanes can be detected both in body tissues and biological fluids such as plasma and urine. Increased concentrations have been detected in oxidized LDL. Isoprostanes are present in human atherosclerotic plaque ((Lawson, J. Biological Chemistry, 274(35), pp. 2441-24444 1999).  Practico (J. Clin. Invest., 100(8), 1997, 2028-2034) discloses that two F2-isoprostanes, 8-epi PGF2 and IPF2alpha-I, are markers of oxidative stress in vivo and are present in human atherosclerotic plaque. Mehrabi (Cardiovascular Research , 43, 1999, 492-499) also disclose that the isoprostane 8-epi-PGF2 is enriched in islolated coronary arteries of patients suffering from cornoary heart disease (CHD). Davi reports that F2-isoprostane 8-epi-PGF2alpha is enhanced in the vast majority of patients with hypercholesterolemia and that vitamin E supplemental was associated with dose dependent reductions.

Lipoprotein(a): is an additional lipoprotein risk factor. It is distinguished form LDL in that, in Lp (a), attached to the LDL partcile is another apoprotein, termed apoprotein(a) (apo(a). This is linked to the LDL particle by a disulfide linkage. It is a highly glycosylated protein. 

Bacterial infection:  has been associated with increased progression of atherosclerosis in rodent model. Invasive P. gingivalis simulates pro-inflammatory cytokines and CAMs in human endothelial cells.

Toll Like Receptors: TLR2 plays a critical role in the profession of arteroscleorisis.

Main Cholesterol Lowering Drugs:

The major types of choelsterol lowering drugs are the following:

Satins (lovastain, pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin):. Statins top an enzyme that controls the rate at which the body produces cholesterol. They lower LDL levels mroe than other types of drugs -about 20-55% and also meorderately lower triglycerdies and raise HDL. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Ezetimibe: reduces the amount of cholesterol absorbed by the body. Ezetimibe can be combined with a stain to get more lowering of LDL. Exteimibe lowers LDL by about 18-25%.

Bile acid resins: bind with cholesterol containing bil acids in the intestine and are then eliminated form teh body in the stool. They lower LDL by about 15-30%. 

Nicotinic acid (niacin): is a water soluble B vitamin that should be taken only under physician superivision. It improved as lipoproteins -total cholesterol, LDL, triglycerides and HDL. LDL levels are usually reduced by about 5-15%. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Fibrates: mostly lower triglycerides and to a lesser degree, raise HDL levels. They are less effective in lowering LDL levels. (“Lowering your Cholesterol with TLC” US Deparmtent of Health and Human Services, December 2005)

Other Therapies

Angiotensin II receptor Inhibitors: help to relax arteries and veins to reduce high blood pressure (a cuase of atherosclerosis). Angiotension is a chemical in the body that narrows arteries. Commo angiotension II receptor inhibitors include Losartan.  

Antioxidants: such as ?-tocopheroal, probucol, butylated hydroxytoluene and dipehenyl phenylenediamine have been shown to decrease LDL oxidation and atheroxlerosis lesion proression in various animal models of atherosclerosis. Although utylated hydroxytoluene and diphenyl phenylenediamine are effective in the prevention of atheroxclerosis in animals, toxicity limits their utility in humans. Thus, supplementaiton with antioxidant nutrients may be a better approach in the prevention of atherosclerosis. Doses of vitamins E and C in excells of the recommended dietary allowances are well tolerated. Alpha Tocopherol is the most prevalent and biologically active form of vitamin E. 

HSD1 inhibitors: Macrophages in the atherosclerotic lesion express HSDA1. This enzyme appears to amplify the effects of gluccorticoids on atherosclerosis since blockage of HSDA decreases inflammatory tone. HSD1 inhibitors counter regulates inflammatory genes.